EVALUATION OF PROGNOSIS AND EFFICACY OF THERAPY FOR NEUROBLASTOMA PATIENTS BY QUANTIFICATION OF METHYLATED DCR2 GENE PROMOTER IN SERUM DNA

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Background: Detection of tumor specific epigenetic alterations using serum DNA has been reported as a reliable and non-invasive strategy for tumor assessment, especially for pediatric cancer patients who cannot easily undergo an invasive examination, because serum DNA predominantly originates from tumor-released DNA in cancer patients. Aberrant hypermethylation of the DCR2 gene (DCR2) promoter has attracted increasing attention because of its close association with rapidly progressing neuroblastomas (NB). Here, we assessed the utility of DCR2 promoter metbylation status as a prognostic factor and indicator of therapeutic efficacy in NB patients using their serum DNA.Methods: We evaluated the ratio of a methylated-DCR2 specific sequence (MVI) and a reference sequence (R) located in the DCR2 promoter in 86 NBs, 18 of which bad MYCN amplification (MNA) using their serum and tumor DNAResults: Serum DCR2 M/R ratios were strongly correlated with those in the tumor (r=0.67;p=0.002). DCR2 hypermethylation was associated with stage both in the whole NB group and in the non-MNA NB group (p<0.001),and patients with DCR2 hypermethylation showed significantly poorer 5-year EFS both in the whole NB group (43% vs. 84%; p<0.001) and in the non-MNA group (12% vs. 96%; p<0.001). Among 5 DCR2-methylated patients whose clinic-Al courses were followed, serum M/R ratios were dose to zero in the patients that experienced remission, whereas they greatly increased in the relapsed patients.Conclusions: Serum DCR2 methylation status is a useful biomarker for predicting a poor prognosis and determining therapeutic efficacy in NB, especially in non-MNANB patients. This method will help to identify NB patients with a poor prognosis, to determine the appropriate intensity of chemotherapy and to evaluate novel therapies.